Traumatic brain injury (TBI) accounts for up to 20% of surviving casualties during military combat. In the Veteran population, clinical studies have identified TBI as a significant risk facto for alcohol use disorders. What could underlie the propensity for TBI victims to become vulnerable to alcoholism? The neuronal response of the brain to injury can perturb normal neuronal function, e.g. alterations in neural connectivity, abnormal plasticity and neuronal network dysfunction. TBI patients who relapsed to alcohol abuse had a greater frequency of brain lesions involving neural circuits that mediate aspects of addictive behavior. Remodeling of dendritic spines (the major site of neuronal communication) accompanies synaptic modifications under pathological conditions, such as TBI. Preclinical studies of post-TBI dendritic spine remodeling and synaptic modification have indicated that TBI is capable of inhibiting anatomical manifestations of neuronal plasticity. Importantly, evidence of disrupted dendritic structure has also been demonstrated in rats with altered ethanol sensitivity. Likewise, rats lacking the ability to regulate synaptic organization have reduced ethanol tolerance. Together, these data demonstrate the relationship between impaired synaptic function, such as that occurring after TBI, and sensitivity to ethanol exposure. There is a clear need to find effective therapies to improve the quality of life of TBI victims. Th ability of environmental enrichment (EE) to modulate dendritic complexity, spine development and behavioral improvement in animal models has been well-established. Increased functional recovery from TBI in rodents has been demonstrated following EE exposure, with associated enhancement of dendritic density. Importantly, EE has been shown to provide protective effects against alcohol abuse susceptibility in rodents. Together, these data suggest that re-establishment of synaptic signaling using EE can have significant effect on behavioral outcome and advance the progress of rehabilitation research. The objective of the current application is to examine the effects of non-contusive TBI on synaptic function and development and the resulting consequences relating to synaptic and behavioral sensitivity to ethanol. The use of environmental enrichment will be explored as an intervention to reduce/reverse the effects of TBI on ethanol sensitivity. The overall hypothesis of this application is that non-contusive TBI will impair synaptic function leading to increased sensitivity to ethanol, which can be reversed by environmental enrichment. We will test this hypothesis using the following specific aims: 1.) Determine the effect of non-contusive TBI on dendritic arborization and synapse formation and function in brain regions that mediate ethanol sensitivity (by quantifying dendritic branching/complexity and spine number/density, as well as activation, expression and distribution of candidate synaptic proteins after injury using confocal analyses and synaptosome preparations) 2.) Determine the effect of non-contusive TBI on acute and chronic ethanol sensitivity (by measuring the activating, sedating and addictive properties of ethanol in the post-TBI period), 3.) Evaluate the efficacy of environmental enrichment in reversing the effects of non-contusive TBI on ethanol sensitivity by improving/restoring synaptic development and function. PUBLIC HEALTH RELEVANCE: Armed forces personnel face a disproportionately increased risk of traumatic brain injury (TBI). Although TBI symptoms may be mild or even undetected, long-lasting behavioral consequences may result in the post-TBIperiod. Notably, among the Veteran population, those with TBI demonstrate increased rates of alcoholism and drug use. Alcohol sensitivity can be altered by TBI-induced disturbances in neural circuitry, making TBI a risk factor for alcohol use disorders. Thus, the proposed project aims to address the critical need to understandhow TBI can disrupt neuronal networks that lead to alcohol use disorders. More importantly, in order to uphold the mission for VA patient care and rehabilitation, the proposed project seeks to evaluate rehabilitation interventions that may effectively reverse the detrimental effects of TBI on neuronal communication and alcohol sensitivity.